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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 26, 2002

A Race to the Bottom

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Posted by Derek

I've already spoken of my disdain for "method of treatment" patents, the claiming of entire biochemical pathways for their medical use. It's something that you never used to see, even though US patent law has long allowed it. But in recent years, an increasing number of these applications have shown up, and they're starting to become issued patents. One of them issued on Tuesday. It's a big one, and it's going to cause a massive legal tangle.

I want to distinguish such patents from the standard "use patents" that companies file on a compound class when they discover a new use. I've no problem with that at all, since it relates to specific chemical entities and what they're good for. A patent claim that "3-aminothingamabobs are useful for the inhibition of whateverase enzyme" is fine with me, as is one that says that "3-aminothingamabobs are useful for the treatment of diabetes." Such patents will have to enable the claims, by backing them up with data showing that the compounds really do inhibit the enzyme, or really do lower blood sugar.

But the kinds of claims that are sending us toward a huge intellectual-property train wreck read like this: "Treatment of disease through inhibition of whateverase enzyme." Note that this claim doesn't address any chemical matter at all - it's similar to a business-method patent of the kind that have been driving technology companies crazy. In effect, this claim says "If you come up with a drug that works through this pathway, you infringe our patent. It doesn't matter if you were looking for something that worked that way or not. It doesn't matter if your compound has six other modes of action. And it doesn't matter if you even knew how it worked when you developed it."

Such patents have come to the drug industry's attention over the last few years, and there have been some local legal skirmishes. But this latest one could start the all-out battle. It covers the use of a cell signaling protein called NF-kappaB (NF-kB, with that "k" more properly in a Greek font.) That one's involved in regulation of genes that are extremely important in inflammation, cell death, and cancerous states. The list of diseases that have an NF-kB component is therefore impressive: cancers of various types, atherosclerosis, osteoporosis, arthritis and sundry other autoimmune diseases, septic shock, and so on. Here's a diagram of its main functions that will be impressively incomprehensible without some cell biology background, and here's a more extended review of the field if you're up for it.

I've no idea of how many academic research groups are working on this, but it's a heap. And in industry? How many drug companies have compounds that hit NF-kB? Well, that figure has been more exactly determined for us by the sole licensee of the new patent, Ariad Pharmaceuticals. They have sent letters to over 50 companies whose marketed or developmental compounds appear to work (at least partially) through that pathway. And they want money from all of them. Right now.

This patent's history goes back to 1986 - the earliest filing in its history is from January of that year, although the issued patent, for reasons that make my head hurt to go into, has an official filing date of 1995. That's an awful long time for an application to be kicking around the patent office; the file wrapper dealing with its prosecution history must be something to see. And I can guarantee that plenty of people are going to ask to see it, starting with the legal department at Eli Lilly.

Ariad had a lawsuit fueled and on the pad, and as soon as their patent was issued, they launched. In fact, the Business Wire press release about the lawsuit went out before the one about the patent, which shows you where Ariad's priorities are. They claim that two of Lilly's biggest products, Evista for osteoporosis and Xigris for sepsis, both work through NF-kB (and there's little doubt that they do, at least partially.) Therefore they're demanding royalties, and pronto. Lilly had ignored Ariad's previous requests for a licensing deal, according to the Wall St. Journal, which moved them up to the exalted position of First Target. The other fifty companies can presumably expect the same treatment if they don't get on Ariad's good side.

Is this going to work? I fervantly hope not, but it's anyone's guess. Almost all my colleagues that I spoke to today said "Oh, come on" to the idea that anyone could legitimately patent all the NF-kB pathways, but the patent runs to a relentless 203 issued claims. It was written carefully and comprehensively. My informal survey group didn't think much of Ariad's chances in court, either. But the company points out, correctly, that they'd be foolish to go ahead without some informed legal opinion saying that they can win.

Ariad's CEO, Harvey Berger, has this to say on their web page:

"We are focusing in 2002 on realizing the value of our intellectual property portfolio,
especially our patents related to NF-kB. . . We are the exclusive licensee
of this pioneering technology and are committed to creating value for the distinguished
team of inventors including two Nobel laureates, their institutions - The Whitehead
Institute, M.I.T., and Harvard University - and our stockholders. Our share of the potential
revenues generated from such efforts should ultimately help underwrite the cost of
developing and commercializing our promising portfolio of breakthrough medicines."

I'd like to furnish my own translation of this statement: "We are focusing in 2002 on shaking down every company we can find, by whacking them over their heads with our mighty patent. This IP windfall could provide us with the huge sums needed to get some of our own ideas to work. But for now, we're going to enjoy stripping the cash from people who have actually been able to develop useful drugs."

Well, as far as I'm aware, I don't know anyone at Ariad. I'm sure that there are some good people there, and I'm sure that some of them are working hard on good ideas. But for now, their company is devoted to a strategy that I think can only hinder medical progress and lead the pharmaceutical industry into a destructive, wasteful, patent war. Ariad should be ashamed, and MIT, Harvard and the Whitehead Institute, the assignees of the patent, should be ashamed to let them go out and do the dirty work for them. Because if they win this, everyone's going to follow suit. They'll have to. And I'm not sure I'm going to be able to stand working in an industry that looks like what that will lead to.

Comments (0) + TrackBacks (0) | Category: Patents and IP

June 25, 2002

Blowups Happen

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Posted by Derek

More details on the Pfizer accident have been released. The initial reports of a fire in the research labs were only correct insofar as all of a pharmaceutical company's facilities are used for research. This was a large-scale affair in a chemical storage area next to a pilot plant, not something that happened in someone's fume hood. I've been unable to find out what solvent or reagent set off the blaze, but it sounds like something that's intrinsically reactive (like a solution of some organometallic reagent.)

Chemical research is a hazardous job. Not as dangerous as, say, coal mining, but there are some real risks. Everyone who's worked in the field for a few years will have stories to tell of accidents that happened in their lab, or down the hall. Most of these stories have reasonably happy endings, but some, inevitably, don't.

You can minimize the risks with attention and intelligence. Almost all the bad accidents I've been around in research labs have grown out of poor decisions: how to set up a reaction, how large to run it, what reagents to use and how. It lets other chemists think "that wouldn't have happened to me," and often, that's true. The two worst accidents I can think of at my current company certainly would not have happened to me, for example.

But that's not always the case. Some bad things just happen, and when you're surrounded by flammable solvents and air-reactive reagents, a small bad thing has the potential to become a large one very quickly. The key is to be ready for what could happen, know how to deal with it, and keep it from getting worse.

You can have your training courses, lab inspections, safety meetings, your standard operating procedures. None of these will protect you, though, from every possible contingency, from random chance or invincible human error. I don't know what the root cause of the Pfizer explosion was, but I assume that it will be determined, and steps will be taken to keep it from happening again. That's a good thing, don't get me wrong - one more accident that's less likely to happen is always a good thing. But there are others out there, and it's one of our jobs as chemists to realize that and be ready.

Comments (0) + TrackBacks (0) | Category: Life in the Drug Labs

June 24, 2002

Another Shot

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Posted by Derek

Little time to blog tonight - I was out at a celebration of another milestone in a compound's development. I've been to a lot of these over the years, and the reason is that you have to celebrate what things you can. If you wait until the compounds hit the pharmacy shelves, you could be in for a long wait.

I've never worked on a project that's led to an actual product - it's possible to go an entire career without that happening. I can think of one, maybe two of my projects in 13 years that have progressed to having a human being put the compound into their mouth.

What happened to the rest? Most didn't make it to the clinic at all. They ran into trouble early, when we couldn't get improved compounds that were even worth continuing with. Or they ran into trouble late, when we tested then in longer toxicity assays and bad things happened to the rats. Others were recommended for development, but only formally - the project ended, a compound was picked, but by that time the reason for the project's existence had evaporated, and the whole thing died on the vine.

Even the things I've had go up to human trials didn't make it beyond phase I (safety.) I haven't ever had an actual sick person take anything I've worked with; that's Phase II. I'd be happy to speculate on the chances of that happening in the next few years, but only if I could think of a way to do it without giving away information (which I don't think is possible.)

Drug companies guard information about their pipeline very closely, and for the most part the only information that gets made public is what they want their competition (or Wall St.) to see. We all spend time wondering about what the heck the folks are up to at the other companies. . .are they celebrating? Going out to dinner? Still working late at night trying to get that far? Or are they filing away another set of lab notebooks, and starting new ones with another project's title on the spine, hoping that this one will work out, for once. . .

Comments (0) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs

June 23, 2002

Stupidity, But Not the Dangerous Kind

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Posted by Derek

After going off on the Weekly Standardon the 11th about the ridiculous miracle-cancer-cure ad they accepted, I see that there's one nearly as stupid in the latest National Review.Fortunately, it's not a particularly dangerous one.

It's for a book that touts a zillion uses for hydrogen peroxide, that wonder chemical that apparently will do everything except housebreak your dog. The good part is that it doesn't actually say that you should drink the stuff to cure cancer, and that's enough for me to hold my fire. If someone gets ripped off because of curiosity about new ways to simultaneously clean their refrigerator and soak their feet, I won't lose much sleep over it.

Of course, there have been various oxygen-therapy yahoots promoting peroxide and worse for years, and many of them claim to cure cancer (and whatever else you've got, though they don't seem to do much for the Heartbreak of Gullibility.) I once saw a come-on that impressed me greatly, promoting some sort of superoxygenated water as a way to get rid of free radicals in your body. That's kind of like selling gasoline-filled fire extinguishers, chemically speaking.

There's not too much good you can do with household hydrogen peroxide, but (fortunately,) not much harm, either. But I worked in a lab once where we had fairly good quantities of the 90% stuff, back in the days when it was more widely available. Now that material could be a real agent for change in your life. We had a spiffy chain-mail glove set that we used to pick it up, and donning those tended to concentrate your mind on the task at hand. . .

Comments (0) + TrackBacks (0) | Category: Snake Oil

June 18, 2002

Save Your Tears

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Posted by Derek

Having unloaded on the Weekly Standardlast week, I now find myself taking aim at the Wall Street Journal. Pretty soon, I'm going to be in the pundit equivalent of Albania (as was,) having ditched my every natural ally.

But it has to be done. The Journal has an editorial today on the Imclone situation - an long impassioned one that starts from false premises and draws incorrect conclusions from them. Let's excerpt the thing:

After starting off by expressing sympathy for cancer patients (and no sympathy for Sam Waksal or Martha Stewart, all perfectly defensible positions,) the editorial calls for "focusing on the FDA's role in this fiasco. . .while Imclone has not produced a study of the size and type the FDA appears to want, the larger truth is that Erbitux continues to show promising results iin small trials."

Note the "appears." Actually, it "appears" that the FDA made its requirements for clinical trials very clear, and it was Imclone that obfuscated. The dispute, which came to light during the recent congressional hearings, centers on the Phase II trial, a combination therapy of Imclone's Erbitux and the current chemotherapy agent irinotecan for colorectal cancer. Originally, as of August 1999, patients were going to get the combination of the two drugs only if their disease had still progressed after two cycles of irinotecan alone. Imclone amended this in October to allow combination therapy after any irinotecan treatment at all, and it appears that the FDA didn't completely catch on. And as it turned out, this plan muddied eventually the data thoroughly enough to make it hard to see if Imclone's drug did anything at all. But it sure did speed things up, which seems to have been what really mattered.

Harlan Waksal of Imclone maintained that they didn't mislead anyone. Minutes of a key meeting in August of 2000, though, showed that the FDA was still under the impression that the original rules applied, and no one from Imclone bothered to correct them. Even when Imclone got "Fast Track" approval in January of 2001, the FDA letter shows their decision was based on the original clinical protocol. No one from Imclone said a word.

And the "larger truth" is that small trials don't mean much. You want meaning, you run a large trial, and you run it the right way, with a design that's capable of distinguishing your drug's effects from random clinical noise. Imclone set everything up to run the fastest, cheapest trial they thought they could possibly get away with, putting the approval of their drug at risk by doing so.

Back to the editorial: "Apparently, the FDA would like Erbitux to show "single-agent activity," even though there is good reason to believe it may work better in combination with traditional chemotherapy drugs." Well, these good reasons turn out to be largely propaganda. Imclone's colorectal cancer trial, as detailed above, relied on giving Erbitux as a combination therapy. When they asked for fast-track approval status, the FDA did indeed get recommendations to turn them down, since the drug had never been tried as a stand-alone therapy. Imclone made great protestations that their drug was not effective by itself, that it had synergistic effects with irinotecan, and that it would be downright unethical to run a trial as a monotherapy. The FDA bought it, and gave them fast-track.

But the data that Imclone backed all this up with wasn't from colorectal cancer patients - it was from renal cancer, which is a very different disease. In January 2001, the FDA (feeling that they'd been had) told Imclone that they needed a monotherapy trial, which they ran. You wouldn't know that from the Journal's editorial, would you? But they ran it in the quickest, shoddiest way possible, with a total of only 57 patients. Six of them responded to Erbitux as a single therapy, but the small number of data points made the results a statistical hairball. Maybe it worked, maybe it didn't.

Sam Waksal told Bristol-Meyers Squibb that this was good news, and that the FDA was pleased with it - but the agency has no record of ever having seen the data at that point, and "pleased" wasn't the right word when it finally showed up. Remember, this study could have shown that Erbitux worked by itself, which would have surprised people after Imclone's earlier statements, but would have been strong data for approval nonetheless. Or it could have confirmed their contention that the drug wouldn't work solo. It did neither, undermining both arguments.

"Too often," the Journal says as the editorial goes into the home stretch, "the FDA simply isn't clear about what a drug like Erbitux has to do to prove itself effective. . ." On the contrary, at least in this case. The record shows that the FDA was quite clear about what it wanted, and informed Imclone in a timely manner. The record also shows that Imclone misled the FDA, their partners at Bristol-Meyers Squibb, and their stockholders at almost every opportunity.

I understand the Journal's reflexive small-government postion, and I sympathize with it most of the time. But this isn't the big regulatory agency beating up on a poor company that only wants to help sick cancer patients. This is a company with their eye on their own stock options, playing games with the data to try to get their drug through as quickly as possible. They took stupid, unacceptable risks by doing so. To use the Journal's formulation, they played these games with the health and hopes of the terminally ill. I've no sympathy for Imclone at all. No one should.

Comments (0) + TrackBacks (0) | Category: Cancer | Clinical Trials

June 16, 2002

A Strange Compound, In Strange Places

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Posted by Derek

A recent paper (Ang. Chem. Int. Ed.41 1740, for those with chemistry libraries at hand) illustrates some interesting things about "natural" and "unnatural" compounds.

It's well known that polychlorinated molecules (DDT, PCBs and others) are quite stable and persistent. Glenn Reynolds over at Instapundit stirred up some folks a few days ago with a reference to DDT, but no matter whose views you subscribe to, there's no denying that the stuff hangs around. One reason is that the compounds are quite lipophilic - they don't sit in aqueous solution waiting to react with things, and they tend to accumulate in lipid tissues of animals, which takes them out of circulation. Another reason is that polychlorinated compounds just aren't all that reactive in general; they're poor substrates for many standard reactions.

(As an aside, that's one of the reasons that the atmospheric effects of chlorofluorocarbons took such a long time to be recognized. These compounds are almost completely unreactive under biological conditions, and not much more lively under even forcing artificial ones. But no one had thought much about what would happen if they got into the upper atmosphere, where they could be hit by hard ultraviolet, the sort that doesn't make it to the ground. . .)

At any rate, there's been a clear distinction between polychlorinated man-made compounds and others which occur in nature. There are thousands of them, actually, many made by marine organisms (who have plenty of chlorine, bromine, and iodine to play around with in seawater.) These tend to be more water-soluble and reactive, though, and haven't been found to persist in tissues.

Until now, it seems. The paper I referred to gives leading references to an odd compound called Q1. It's been found in biological samples all over the world, and sometimes in some seriously large concentrations. Analysis showed it to have an empirical formula that doesn't correspond to any compound that's ever been reported. The paper has the real structure, confirmed by two different syntheses, and it's a rather odd-looking chlorinated bipyrrole.

The thing is, no one knows where the stuff comes from. And (for once) it doesn't appear to be us, since the compound was completely unknown until now. Nothing even that close to it is produced industrially. The closest things are some other halogenated pyrroles found in some marine bacteria, lending credence to the theory that this is a biogenic material. No one's found one like this, though.

As I've spoken to people about this, reactions have been interesting. Most of my fellow chemists have found the structure intruiging, and the idea that it's a natural product pretty weird. But I've had a couple of colleagues react by saying "That has to be coming from people." When I point out the features mentioned in the paragraph above, it doesn't seem to convince them. "It'll turn out to be from us," I've been told.

Well, I'm with the authors of the paper in not thinking so. Nature's got a lot of surprises, and making something that looks just like a synthetic pollutant doesn't seem like too much of a stretch. Think of it as a polychlorinated prank, pulled off by some dinoflagellate or red algae.

Comments (0) + TrackBacks (0) | Category: General Scientific News

June 13, 2002

The Company You Keep

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Posted by Derek

Here's more info on the "Dr. Burton" mentioned in the egregious Weekly Standard advertisement (see the Tuesday, 6/11 post below.) This is courtesy of the invaluable Quackwatch. This is surely the same person. As far as Burton's methods go, what the book that the advertisement is selling is supposed to do for you, other than tell you more stories about his miracle cures, is hard to imagine. It's not something you're going to whip up at home (although stuff you could whip up at home would do just as much good, it seems, and cost less, too.)

As for Johanna Budwig, a Google search of that name will give you hours of reading, if not of reading pleasure. Flax seed oil and cottage cheese seem to the the two constituents of her miracle diet - there, I've saved you the $19.95 that those slimeballs were charging for their book.

I've had opportunity to study the effects of various lipid constituents on biological targets in the body, and I'd certainly not deny that you can effect a lot of interesting biology by varying the lipid profile of your diet. But keep cancer from even happening? I think not.

No response from the Weekly Standard folks yet (I sent them the first article below.) I'll be quite interested to hear what they have to say, if anything.

Comments (0) + TrackBacks (0) | Category: Snake Oil

June 11, 2002

And All For a Little Money

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Posted by Derek

Today I wanted to cover a particular intersection of medicine, commerce, and politics in the June 10th issue of The Weekly Standard.I've read the magazine on and off since its inception, and enjoyed it. I often agree with its editorial stance, and when I don't, I can usually see what the writers are up to, and how a reasonable person would come to their conclusions.

What caught my attention this time was something I disagreed with most strongly, but it wasn't an article. It was an advertisement on page 15, titled "Black Listed Cancer Treatment Could Save Your Life." Well, I earn my living by trying to find treatments that could potentially save people's lives, so headlines like that catch my eye.

But not in a positive fashion: for many years, I've kept an eye on all sorts of medical quackery, of which there is an inexhaustible supply. I'm pretty sure that I've seen this ad before, actually. For all I know, I've seen it before in The Weekly Standard.But I'd had a long day at the lab when I picked up this issue, and I was in a mood to read the whole thing.

It repays inspection. I found that in 1966, the "senior oncologist at a prominent New York hospital" developed some miracle serum that "shrank cancer tumors in 45 minutes!" And after another 45 minutes, "they were gone." (How this was determined using 1966 technology is left as an exercise for the reader, I suppose.) Who is this wonder-worker, and at which hospital did he work? The ad glancingly refers to him as "Dr. Burton," but goes on to relate that he was shut down by the FDA and forced - yes, forced - to leave the country, "where others benefited from his discovery." After their checks cleared, presumably.

We then switch to one Dr. Johanna Budwig, a "six-time Nobel Award nominee." Now an instant sign of fakery, as if another one were really needed after that first paragraph. No one knows who's really up for the science Nobels; the Academy isn't telling. When someone brags about being nominated for a Nobel in one of the hard sciences, it's time to head for the exits. I might as well say that I'm a six-time nominee for the NBA slam-dunk championship - hey, if I'd sent them postcards every year asking to be included, then why not?

"Dr. Budwig's" story is similar to Dr. Burton's, only she found a miracle diet that prevents cancer from even occuring. But (and you knew this was coming) she was "blocked by manufacturers with heavy financial stakes!" Hey, did they check Dr. Burton out? Seems like he'd have a reason to keep this competitor off the market. . .

Well, the ad goes on and on, and if you've seen one of these, in some ways you've seen them all. The whole thing is selling a book called "How to Fight Cancer and Win." Natural healing, miracle cures, secret breakthroughs they don't want you to know, all backed up by testimonials from people with initials for last names. One "Molly G" says that the book "has information I've never heard about before," and I find that statement the most believable thing on the whole page.

It's just another cheesy scam, another rip-off aimed at people who are scared of getting cancer, people scared that they might have it. . .or at people who really do have it and are scared that they're going to die. A fine group of customers to remove cash from. The publisher gets the money and a live mailing address (well, for a while), to sell to every other quack who needs a fresh group of the desperate and frightened.

So, what I'd like to know is, what is the Weekly Standard doing profiting from this slimy business? Now, I know that opinion journals need ads, and they never have enough. There are 44 numbered pages in this issue of the Standard, and there are only five pages of advertisements. That's probably about enough to pay for the coated paper. But I also know, as does everyone else, where the money is coming from: Rupert Murdoch, who felt it worth the inevitable steady losses to promote political views he agrees with.

More power to him, I say. But how are those views advanced by their proximity to sleazy ads for amazing cancer cures? I'm sure the advertising manager for the Standard would rather fill the issue up with ads for BMWs and single-malt whiskey. Does the magazine really hit the miracle-cure demographic? And does it really want to look like that's the one it reaches? Does News Corp. need the money this badly?

There's the practical argument. The impractical one is that taking money in exchange for giving these snake-oil merchants space is very close to immoral. I'm well aware of the precedent set (for example) by David Horowitz, trying to get his anti-slavery reparations ad placed in college newspapers. As was pointed out at the time, though, a newspaper or magazine is free to accept or reject any advertisements it feels like. (And a rejected advertiser is free to say what he thinks about the refusal!)

But this sort of ad isn't selling an argument - it purports to be selling scientific facts that will save your life. And these "facts" are, as far as I'm concerned, life-threatening bullshit. Would the Standard take an ad from the Scientologists? Would it take an ad from a throw-away-your-crutches faith healer? After this one, why not?

Comments (0) + TrackBacks (0) | Category: Snake Oil

June 6, 2002

Adam Smith Goes Pharmaceutical

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Posted by Derek

As readers will have noted in my comments on drugs like Clarinex and Nexium, I certainly don't think the industry I work in is always a one-hundred-percent benefactor of humanity. Drug companies are here to make money, and (like any business) they're trying to make the most money they can, consistent with their tolerance for the chance of losing it.

The much-written-about report on innovation in the drug industry (PDF here) turned out, on inspection, to be much less confrontational than I had feared. The authors point out, correctly, that pharmaceutical companies are reacting rationally to their environment. Big, money-making drugs are coming off patent, and not enough new ones have been discovered in the last few years to take up the slack. Therefore, the companies will do whatever they can think of to keep the profits coming in for as long as possible.

That includes stepping up the marketing campaigns for what drugs they have. It includes ripping off their own expiring profit center drugs (as in the two mentioned above,) and doing whatever they can to get patients to ask for them and physicians to write for them. And that includes all sorts of schemes to delay generic competition. Some of them are bare-knuckled, but within the letter of the law (fighting patent claims.) Some are apparently legal, but have a certain shady aura around them (such as paying generic companies to go away.) And still others, like this accusation against Bristol-Meyers Squibb, are (if true) flat-out illegal.

It's capitalism in action, and it's not always - not even usually - a pretty sight. The same sorts of things go on in every other industry, in any number of variations. I think the same thing about individual economic competition, for that matter. One reason I like capitalism better than the other schemes that have sought to supplant it is that it seems to me to line up more closely with human nature. Not an original thought, but its validity is why it's so well known.

People are going to act in their own interest, to serve what they see as their needs and desires. You can't get rid of it, so you might as well set things up so they do some good while they're at it. Wouldn't it be more efficient if everyone worked that hard for the common good, though? Sure! Should some other zoological phylum develop intelligence, maybe they can give it a try. We, as far as I can tell, are wired for what we're doing.

And so are companies. Wouldn't it be more efficient if all of us in the drug industry just stopped trying to outdo each other? Open up the labs, put all our compounds in one gigantic screening file, pool our efforts? Well. . .it's a tempting idea, in some ways. But what keeps us going is the competition, the knowledge that (like the sharks we are,) that we have to keep moving or die. I fear that a Monolithic MegaPharm would become so bureaucratized and lethargic that whatever good came of getting larger would be more than canceled out. Some of the large merged companies we have now are showing signs of this disease as we speak.

Knowing that other people are working on the same targets keeps us moving. The ticking clock of patent expirations, the arm-wrestling with the regulatory agencies, the demands of shareholders keep us moving. I think the best thing to do would be to, again, arrange it so that the maximum amount of good gets done while we're out there pursuing our own agendas.

That means that I wouldn't, frankly, object to making it harder to put drugs like Clarinex, Nexium and so on on the market. If I were the FDA, I'd raise the bar in such cases for advantageous efficacy, and if I were an HMO, I'd raise it for what I'd reimburse. But at the same time, I'd make it easier to find and sell new drugs, so there would be less incentive for all these activities that don't lead to any real benefit. Faster regulatory approval, no method-of-treatment patent claims, more incentives like the orphan drug designation, some sort of tort reform: all these would help.

It boggles the mind, the amount of effort and ingenuity pulsing through a high-tech area like pharmaceuticals. But political grandstanding about the evil drug companies, schemes to clamp down good and hard on them: these could wipe out the crazy risk-taking that's at the heart of the industry. Whack the ones that get out of line, sure. But while you're doing that, set the system up so that we can whack on each other with even more ferocity than ever. That's where the good stuff comes from.

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June 4, 2002

A Clean Lab is A Happy Lab

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Posted by Derek

I've been throwing away piles of junk from my desk the last few days, and I can now see the darn thing again. My fume hood and lab bench need a bit of organizing, too, but they don't get as bad as they used to when I worked in them full-time. The desk, though, has always been bad, and now it gets to its final maximum-entropy state more quickly than ever.

I'm not one of those people who can automatically find things in the shaggy piles of paper, either. Well, I can for a while, but when I start losing things I know it's time to clean up. A majority of the paper goes straight into the recycling bin; some of it should have gone straight there without visiting my desk at all. Some of the photocopied papers get filed (I still have some I copied off when I was an undergraduate, and boy, do they look raggy. Makes me feel old every time I get one of them out.)

There's reason to be suspicious of people who keep incredibly clean desks, but I can see how someone would like to. The folks I really wonder about are the ones with spotless and well-organized labs. I just can't see how you can get a reasonable amount of work done and take the time to keep everything shining simultaneously.

Back at my former company, high school groups would come in for tours once in a while, and they were usually struck by the condition of my lab. That's because I didn't clean up for them - no Potemkin in a lab coat, me. "This is the real thing," I'd tell them. "Those other labs you'll see today, the ones that look like you could make tuna salad in there and eat it right off the bench? They're not doing enough work."

I'm reminded of the (apocryphal?) story of Alexander Fleming taking a tour of one of the first large-scale penicillin operations. Everything was gleaming (the closer you get to putting stuff in the bottle, the more gleaming it should be - that's why my labs have been such stys.) Fleming was impressed, but pointed out that he never could have found penicillin under such conditions!

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June 3, 2002

When Natural Selection's Through With You - Part II

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Posted by Derek

Another useful paper (Science 296, 1276) has come out on the mechanisms of aging. Ever since the 1950s, the idea of accumulating free radical damage has been a strong contender, to the point that it's been absorbed into popular culture. All the free radicals needed for this damage to take place are produced by our own metabolism: oxygen is pretty fierce stuff to handle.

There's a good amount of evidence that this theory is at least partially correct (such as the existence of enzymes like superoxide dismutase, SOD, whose only function in life is to get rid of one of those reactive oxygen-derived species.) And now there's more. The latest work involves mice with a mutated form of a particular helicase protein called Xpd. This is an important part of the DNA-RNA transcription machinery, and it's also important for a variety of DNA repair, nucleotide excision. The dual function makes sense; both processes involve unwinding the double helix so enzymes can bind to it directly.

There's a human genetic disease, trichothiodystrophy (TTD) that involves alterations in Xpd function, and the research group was trying to come up with a mouse syndrome that would mimic it. They got it, but the mice also shown signs of accelerating aging (gray hair, osteoporosis, loss of appetite, shorter life span.)

That would seem to be the end of the story: if you can't repair DNA damage, you age quicker. But another experiment has already been done to completely knock out a closely related protein called Xpa, and that knockout completely wipes out the ability to do nucleotide-excision repair. But those knockout mice don't show signs of premature aging! So what's going on?

One way to find out would be to take those Xpa-knockout mice and introduce the Xpd mutation into them. This group tried that experiment, and got the same premature aging, but in much more severe form. What might be happening, then, is that the total effect of DNA damage on gene transcription might be the aging factor. If you can still read off the DNA, damaged or not, then cell activity can still muddle on (as in the Xpa knockouts that don't show premature aging.) If your gene transcription keeps getting stalled out, as in the Xpd mutants, then you're in trouble. The cells involved end up dying (by programmed cellular suicide, apoptosis) or damaged. If you have both mutations at once, the defective DNA that accumulates is unwound and exposed for even longer periods, setting both those processes in motion even faster.

We're getting closer to making a coherent picture out of this - other knockout experiments shed some light on it, and others are no doubt in progress. As for what to do about it, that's a different question. The close association of aging with DNA damage means that there may well be a tradeoff between oncogenesis and aging - you can keep your cells alive for a long time, at the risk of developing cancer, or you can have them kill themselves off at the first sign of trouble, which helps to cause aging. We'll have to tread carefully, but there would still seem to be some wiggle room in there.

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It's Not Pretty, But It Works

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Posted by Derek

Charles Murtaugh has an interesting piece on drug discovery, and invites me to correct any misstatements that he may have made. Hey, under my no-sparrow-shall-fall policy on mentions of drug discovery in the blogosphere, I'd have put my oar in anyway.

Charles's main point is exactly right: that discoveries in the medical/biotech field are often way out in front of any understanding of why they work. To my mind, it comes down to the distinction between engineering and basic research. An engineering problem is one that's largely constrained by known limits; its solution is the best that can be achieved within those limits. Want to make a Mach 5 airplane, bridge the Bering Strait, shrink a chip by a factor of ten? Here are the materials that you can work with; here are their properties (and, lest we forget, here's what they cost!) There's room for huge amounts of ingenuity within those constraints, but if you try to get out of them, your work turns into a research project very quickly.

We already know that things can travel at Mach 5, that long stretches of water can be spanned, and that chips can be made very small. It's a question of whether a usable plane, bridge, or chip can be made to do what you want, with the materials you have. At some point, you'll run into the limits of those materials, and the closer you get to those limits, the more basic research gets mixed into the engineering. If you decide that you need something for your airplane wing that has the melting point of titanium and weighs less than aluminum, well, you're going to be at it a while.

The examples that Charles uses in his piece - Wright brothers, Microsoft, Intel - are actually engineering projects, for the most part, which is one reason they sound odd when contrasted with basic research in the medical field. That's because science lives, of course, by finding weird results that are outside current understanding. When something sufficiently unusual comes along, we all jump on it and try to figure out why it does that, what we can use it for, what else acts like that, what happens if you mess with this part over here. . .whoops!

In our corner of it, as Charles points out, you can know that a medicine works without knowing how it works. As far as the FDA goes, if you can prove safety and efficacy (Phase I and Phase II/III trials, respectively,) then you're in, mechanism or not. But even if you know a lot about the mechanism you usually have no idea if what you're trying to do is possible or not.

Will inhibiting angiotensin-converting enzyme lower blood pressure? Can you make a small molecule that will inhibit the enzyme? The answer to both of those is a resounding "yes," as has been established. OK, what if you inhibit that one and neutral endopeptidase - the rationale for trying this is just as reasonable. Can you make a molecule that does it, and will that combination work even better? The answer to the first question is a resounding "yes," again. And the answer to the second, as Bristol-Meyers Squibb found to their sorrow, is an exhausted, resigned "no, probably not."

Of course, knowing the molecular mechanism for a drug helps tremendously in developing it. Most big companies prefer to work on targets that they have such an understanding of, because it helps you set up high-throughput assays to find the good stuff faster. The most frustrating sort of project is one where you have some wonderful effect in an animal model, but no idea of why it happens. You can end up making compounds and taking directly into the animal model, which is the old-fashioned (and slower, and more costly, and harder to optimize) way of doing it.

To directly address a question that Charles asks, we do indeed spend a lot of time changing our lead molecules around to see if they work better. It's not quite random, though, since we have a legacy of well-known tricks that have been shown to help in other projects (and a legacy of well-known things to avoid, too.) But once we're inside a given series of compounds, it's true: we just make as many different ones as we can, and let the assays sort 'em out.

He's also right that the full-scale "rational drug design" approach has been a bust, so far. (I talked about this back on February 7.) We just don't know enough yet to get this to work the way it potentially could. And his point about nanotechnology is very well-taken indeed: the whole idea of medical nanotech is predicated on knowing a great deal about exactly what you're trying to accomplish and how to do it, and both those items, unfortunately, are often on long-term back order.

Will they arrive eventually? That's where I get into my odd pessimist/optimist thing again. Long term, I think we really will figure this stuff out. But it'll be a longer term than we'd like, with a lot of twists and turns. Even so, I still see all these problems as eventually yielding to human skill and ingenuity - great big heaps of skill and ingenuity, and piles of time and money. My optimism comes from the first half of that sentence; my pessimism from the second. They coexist, but on different time scales.

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